Captopril, [the compound of the formula I] ##STR1## is an antihypertensive agent inhibiting the angiotensin converting enzyme (ACE). A high number of processes are known for the preparation of this compound. Several possibilities utilize L-proline, and acylate this with 3-mercapto protected-2-methylpropionic acid derivative.
According to one reaction route, the tert-butyl ester of L-proline is acylated with 3-acetylthio-2-methylpropionic acid in the presence of N,N'-dicyclohexylcarbodiimide, the product is transformed into its dicyclohexylamine salt and the latter is precipitated with acetonitrile and recrystallized from isopropanol. In this way dicyclohexylamine 1-[3-acetylthio-(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylate is obtained with a yield of 25%. The carboxylic acid is liberated with a yield of 83%. Then, the acetyl group protecting the mercapto group is removed by means of ammonia in methanol under a argon atmosphere with a yield of 74%. The compound of the formula I is separated as its dicyclohexylamine salt, from which the carboxylic acid is liberated with a yield of 75%. The starting tert-butyl ester of L-proline can be prepared from L-proline in 3 steps (i.e. N-benzyloxycarbonyl-L-proline, yield: 89%; tert-butyl ester of N-benzyloxycarbonyl-L-proline, yield: 93%; tert-butyl ester of L-proline, yield: 77%) and the acylating reagent, 3-acetylthio-2-methylpropionic acid can be prepared from methacrylic acid with thioacetic acid with a yield of 83%. Thus, the total synthesis consists of 8 reaction steps and the total yield is equivalent to 6.7% calculated for methacrylic acid and 8.1% calculated for L-proline, respectively.
According to a further reaction route, L-proline is directly acylated (e.g., following the Schotten and Baumann reaction) in the presence of an alkali hydroxide with 3-acetylthio-2-methylpropionyl chloride. The latter reagent is prepared from the corresponding carboxylic acid with a yield of 60%. Although the acylation step is performed with a yield of about 95%, the dicyclohexylamine 1-[3-acetylthio-(2S)-methyl-propionyl]-pyrrolidine-(2S)-carboxylate is obtained merely with a yield of 33%, and then follows the purification of the salt from isopropanol. Thus, the total yield of the whole Schotten-Baumann reaction is lower than 30%. The carboxylic acid is liberated from the dicyclohexylamine salt with a yield of 83%, then the acetyl group protecting the mercapto group is hydrolyzed by means of aqueous ammonia and the compound of the formula I is liberated on a column containing a cation exchanger with a yield of 42%. Although this reaction route consists of only 5 reaction steps, no improvement could be reached regarding the total yield being equivalent to 5.2% calculated for methacrylic acid, and 10.5%, calculated for L-proline, respectively.
Another problem with processes known in the prior art, such as U.S. Pat. No. 4,105,776, Example 152; or U.S. Pat. No. 5,026,873 (both to Squibb), is that a large amount of a dimeric by-product (15%) is prepared. This unwanted by-product has been identified as a S-acetylated product, ##STR2##
None of the known processes insures an economical method that could be performed simply and with an acceptable yield for the preparation of the compound of the formula I, while minimizing byproduct formation.
Therefore, it was the aim of the invention to eliminate the drawbacks connected with the known processes and to provide a process consisting of only a few reaction steps that can be performed economically on an industrial scale, and which does not result in unwanted by-product, thereby resulting in both high yield and high quality.